The rapidly intensifying search for biologically and medicinally important marine organism constituents has attracted a great deal of interest world-wide. Not unexpectedly, a reassuring number of marine animals, plants and microorganisms are being found to produce promising anticancer substances of unprecedented structural types.
Discovery and synthesis of potentially useful antineoplastic peptides from naturally occurring materials comprises one of the most essential and promising approaches for new anticancer drugs. Of special interest at the Cancer Research Institute of Arizona State University, Tempe, Ariz., are the dolastatins, an unprecedented series of structurally separate linear and cyclic antineoplastic and/or cytostatic peptides which are isolated from the Indian Ocean sea hare Dolabella auricularia. Presently dolastatin 10 and dolastatin 15 represent the two most potent, and hence most important, members of those isolates. While dolastatin 10 has recently yielded to total synthesis (See: U.S. Pat. No. 4,978,744, Pettit et al, Dec. 18, 1990), the corollary problem of devising a total synthesis of dolastatin 15 remained a challenge.
The need for such a total synthesis was further dramatized when a determination of the vast number of Dolabella auricularia that would have to be harvested in order to provide sufficient dolastatin 15 to meet the projected public need was made. Thus, without an economically viable method of synthesis, dolastatin 15 could be effectively barred from consideration for human therapy because of the astronomical investment required for commercial production. The natural substance must be tightly replicated from lot to lot because the entrainment of even a slight amount of unidentifiable impurities in the extracted product could create problems which would prevent the natural substance from meeting the strict uniformity required for the approval by the United States Food, Drug and Cosmetic Administration (FDA) and corresponding regulatory agencies of other nations.
Accordingly, an important need exists for the development of an economically viable and truly replicable procedure for synthetically producing substantially pure dolastatin 15 in sufficient quantities to meet the public demand. It is toward the fulfillment of that need that the present invention is directed.